Malaria is an infectious febrile disease caused by the protozoa of the genus Plasmodium, which are parasitic in the red blood cells, and are transmitted by the bites of infected mosquitoes of the genus Anopheles. The disease is characterized by attacks of chills, fever, and sweating, occurring at intervals which depend on the time required for development of a new generation parasites in the body. After recovery from acute attack, the disease has a tendency to become chronic, with occasional relapses. There are four human species Plasmodium falciparum (P. falciparum), Plasmodium vivax (P. vivax), Plasmodium malariae (P. malariae) and Plasmodium ovale (P. ovale).
Among the various forms of human malaria, malaria caused by P. falciparum, characterized by severe constitutional symptoms and sometimes causing death, is responsible for the majority of the mortality in humans. P. falciparum is dangerous not only because it digests the red blood cell's hemoglobin, but also because it changes the adhesive properties of the cell it inhabits, which causes the cell to stick to the walls of blood vessels. This becomes dangerous when the infected blood cells stick to blood vessels, obstructing blood flow. The disease is prevalent in tropical and subtropical areas of the world including the Amazon region of Brazil, East and Southern Africa and Southeast Asia. According to the World Health Organization World Malaria Report 2011 there were 216 million cases of malaria in 2010 and 81% of these were in the WHO African Region. There were an estimated 655,000 malaria related deaths in 2010 with 86% of the victims being children under 5 years of age.
Malaria has been treated with various drugs throughout recent history including combinations of drugs. However, the emergence of drug resistant strains of malaria has become a significant problem in the treatment of malaria. The WHO recommends artemisinins in combination with other classes of antimalarials (artemisinin-based combination therapies (ACTs)) as the first line treatment for malaria caused by P. falciparum. The emergence of P. falciparum resistant to artemisinins, confirmed on the Cambodia-Thailand border in 2009 and suspected in parts of Myanmar and Vietnam, highlights the critical need for new malaria drugs from novel chemical classes.
Since the original work of Burckhalter (Burckhalter, J. H., et al., J. Am. Chem. Soc. 1946, 68, 1894-1901 and J. Am. Chem. Soc. 1948, 70, 1363-1373), aminoalkyl phenols have been studied extensively as antimalarial agents (See Wiselogle, F. Y., Ed.; Survey of Antimalarial Drugs, 1941-1945, Vols. I and II, Edwards Bros., Ann Arbor, Mich., and Duncan, W. G., et al., J. Med. Chem. 1969, 12, 711-712). Optimization of the original α-(dialkylamino)-o-cresol template led to the identification of WR-194,965 (Schmidt, L. H., et al., Antimicrobial Agents and Chemotherapy 1978, 14, 672-679, Peters, W., et al., Annals of Tropical Medicine & Parasitology 1984, 78, 561-565, and 1984, 78, 567-579) which was profiled in human clinical trials (Karle, J. M., et al., Antimicrobial Agents and Chemotherapy 1988, 32, 540-546). Further modifications involved addition of the known antimalarial 4-aminoquinoline moiety to the aminoalkyl phenol template and led to the identification of antimalarial compounds such as Amodiaquine (Burckhalter, J. H., et al., J. Am. Chem. Soc. 1948, 70, 1363-1373) and Tebuquine (Werbel, L. M., et al., J. Med. Chem. 1986, 29, 924-939). Recently, 3,5-disubstituted-2-aminoalkylphenols with antimalarial activity have been reported (U.S. Pat. No. 7,589,127, issued Sep. 15, 2009 and Powles, M. A., et al., Antimicrobial Agents and Chemotherapy 2012, 56, 2414-2419).
New antimalarial compounds with exceptional potency, high activity against resistant strains, and good safety profiles are still needed.